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Revisión médica por Militian Inessa Mesropovna Última actualización de farmacia el 12.03.2022
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Enfermedades malignas
Ledoxan (ciclofosfamida) está indicado para el tratamiento de:
- linfomas malignos (etapas III y IV del sistema de estadificación Ann Arbor), enfermedad de Hodgkin, linfoma linfocítico (nodular o difuso), linfoma de células mixtas, linfoma histiocítico, linfoma de Burkitt
- mieloma múltiple
- leucemias: leucemia linfocítica crónica, leucemia granulocítica crónica (generalmente es ineficaz en crisis blástica aguda), leucemia mielogénica y monocítica aguda, leucemia linfoblástica aguda (célula madre) (la ciclofosfamida administrada durante la remisión es efectiva para prolongar su duración)
- micosis fungoides (enfermedad avanzada)
- neuroblastoma (enfermedad diseminada)
- adenocarcinoma del ovario
- retinoblastoma
- carcinoma de mama
La ciclofosfamida, aunque es efectiva sola en tumores malignos susceptibles, se usa con mayor frecuencia de forma simultánea o secuencial con otros fármacos antineoplásicos.
Síndrome nefrótico de cambio mínimo en pacientes pediátricos:
La ciclofosfamida está indicada para el tratamiento del síndrome nefrótico de cambio mínimo comprobado por biopsia en pacientes pediátricos que no respondieron adecuadamente o no pueden tolerar la terapia con adrenocorticosteroides.
Limitaciones de uso
No se ha establecido la seguridad y eficacia para el tratamiento del síndrome nefrótico en adultos u otra enfermedad renal.
Durante o inmediatamente después de la administración, se deben ingerir o infundir cantidades adecuadas de líquido para forzar la diuresis a fin de reducir el riesgo de toxicidad del tracto urinario. Por lo tanto, la ciclofosfamida debe administrarse por la mañana.
Dosificación para enfermedades malignas
Adultos y pacientes pediátricos
Intravenoso
Cuando se usa como la única terapia farmacológica oncolítica, el curso inicial de ciclofosfamida para pacientes sin deficiencia hematológica generalmente consiste en 40 mg por kg a 50 mg por kg administrados por vía intravenosa en dosis divididas durante un período de 2 a 5 días. Otros regímenes intravenosos incluyen 10 mg por kg a 15 mg por kg administrados cada 7 a 10 días o 3 mg por kg a 5 mg por kg dos veces por semana.
Oral
La dosis oral de ciclofosfamida generalmente oscila entre 1 mg por kg por día y 5 mg por kg por día para la dosificación inicial y de mantenimiento.
Se han informado muchos otros regímenes de ciclofosfamida intravenosa y oral. Las dosis deben ajustarse de acuerdo con la evidencia de actividad antitumoral y / o leucopenia. El recuento total de leucocitos es una buena guía objetiva para regular la dosificación.
Cuando se incluye ciclofosfamida en regímenes citotóxicos combinados, puede ser necesario reducir la dosis de ciclofosfamida y la de los otros fármacos.
Dosificación para el síndrome nefrótico de cambio mínimo en pacientes pediátricos
Se recomienda una dosis oral de 2 mg por kg al día durante 8 a 12 semanas (dosis máxima acumulada de 168 mg por kg). El tratamiento más allá de 90 días aumenta la probabilidad de esterilidad en los hombres.
Preparación, manejo y administración
Maneje y deseche la ciclofosfamida de manera consistente con otros fármacos citotóxicos.1 Se debe tener precaución al manipular y preparar ciclofosfamida para inyección, USP (polvo liofilizado) o botellas que contengan tabletas de ciclofosfamida. Para minimizar el riesgo de exposición dérmica, use siempre guantes al manipular viales que contengan ciclofosfamida para inyección, USP (polvo liofilizado) o botellas que contengan tabletas de ciclofosfamida. El recubrimiento de las tabletas de ciclofosfamida evita el contacto directo de las personas que manipulan las tabletas con el principio activo. Sin embargo, para evitar la exposición accidental al principio activo, las tabletas de ciclofosfamida no deben cortarse, masticarse ni triturarse. El personal debe evitar la exposición a tabletas rotas. Si se produce contacto con tabletas rotas, lávese las manos de inmediato y a fondo.
Ciclofosfamida para inyección, USP
Administración intravenosa
Los productos farmacológicos parenterales deben inspeccionarse visualmente para detectar partículas y decoloración antes de la administración, siempre que la solución y el envase lo permitan. No use viales de ciclofosfamida si hay signos de fusión. La ciclofosfamida derretida es un líquido viscoso transparente o amarillento que generalmente se encuentra como una fase conectada o en gotas en los viales afectados.
La ciclofosfamida no contiene ningún conservante antimicrobiano y, por lo tanto, se debe tener cuidado para garantizar la esterilidad de las soluciones preparadas. Usa técnica aséptica.
Para inyección intravenosa directa
Reconstituya la ciclofosfamida con inyección de cloruro de sodio al 0.9%, solo USP, utilizando los volúmenes enumerados a continuación en la Tabla 1. Agite suavemente el vial para disolver el medicamento por completo. No use agua estéril para inyección, USP porque da como resultado una solución hipotónica y no debe inyectarse directamente.
Tabla 1: Reconstitución por inyección intravenosa directa
Fuerza | Volumen de cloruro de sodio al 0.9% | Concentración de ciclofosfamida |
500 mg | 25 ml | 20 mg por ml |
1 g | 50 ml | |
2 g | 100 ml |
Para infusión intravenosa
Reconstitución de ciclofosfamida
Reconstituya la ciclofosfamida usando 0.9% de inyección de cloruro de sodio, USP o agua estéril para inyección, USP con el volumen de diluyente que se detalla a continuación en la Tabla 2. Agregue el diluyente al vial y gire suavemente para disolver el medicamento por completo.
Tabla 2: Reconstitución en preparación para infusión intravenosa
Fuerza | Volumen de Diluyente | Concentración de ciclofosfamida |
500 mg | 25 ml | 20 mg por ml |
1 g | 50 ml | |
2 g | 100 ml |
Dilución de ciclofosfamida reconstituida
Diluya aún más la solución reconstituida de ciclofosfamida a una concentración mínima de 2 mg por ml con cualquiera de los siguientes diluyentes:
- 5% de inyección de dextrosa, USP
- 5% de dextrosa y 0.9% de inyección de cloruro de sodio, USP
- 0,45% de inyección de cloruro de sodio, USP
Para reducir la probabilidad de reacciones adversas que parecen depender de la tasa de administración (p. Ej., hinchazón facial, dolor de cabeza, congestión nasal, ardor del cuero cabelludo), la ciclofosfamida debe inyectarse o infundirse muy lentamente. La duración de la infusión también debe ser apropiada para el volumen y el tipo de fluido portador que se infundirá.
Almacenamiento de solución de ciclofosfamida reconstituida y diluida
Si no se usa inmediatamente, para la integridad microbiológica, las soluciones de ciclofosfamida deben almacenarse como se describe en la Tabla 3 :
Tabla 3: Almacenamiento de soluciones de ciclofosfamida
Diluyente | Almacenamiento | |
Temperatura ambiente | Refrigerado | |
Solución reconstituida (sin más dilución) | ||
0.9% Inyección de cloruro de sodio, USP | hasta 24 horas | Hasta 6 días |
Agua estéril para inyección, USP | No almacenar; usar de inmediato | |
Soluciones diluidas1 | ||
0,45% de inyección de cloruro de sodio, USP | hasta 24 horas | hasta 6 días |
5% de inyección de dextrosa, USP | hasta 24 horas | hasta 36 horas |
5% de dextrosa y 0.9% de inyección de cloruro de sodio, USP | hasta 24 horas | hasta 36 horas |
1El tiempo de almacenamiento es el tiempo total en que la ciclofosfamida está en solución, incluido el tiempo en que se reconstituye en 0.9% de inyección estéril de cloruro de sodio, USP o agua estéril para inyección, USP |
Uso de solución reconstituida para administración oral
Las preparaciones líquidas de ciclofosfamida para administración oral pueden prepararse disolviendo ciclofosfamida para inyección en elixir aromático, formulario nacional (NF). Dichas preparaciones deben almacenarse bajo refrigeración en recipientes de vidrio y usarse dentro de los 14 días.
- Hipersensibilidad
La ciclofosfamida está contraindicada en pacientes con antecedentes de reacciones de hipersensibilidad severas, cualquiera de sus metabolitos u otros componentes del producto. Se han notificado reacciones anafilácticas, incluida la muerte, con ciclofosfamida. Puede producirse una posible sensibilidad cruzada con otros agentes alquilantes.
- Obstrucción de flujo de salida urinario
La ciclofosfamida está contraindicada en pacientes con obstrucción del flujo urinario.
WARNINGS
Included as part of the PRECAUTIONS section.
PRECAUTIONS
Myelosuppression, Immunosuppression, Bone Marrow Failure and Infections
Ledoxan (cyclophosphamide) can cause myelosuppression (leukopenia, neutropenia, thrombocytopenia and anemia), bone marrow failure, and severe immunosuppression which may lead to serious and sometimes fatal infections, including sepsis and septic shock. Latent infections can be reactivated.
Antimicrobial prophylaxis may be indicated in certain cases of neutropenia at the discretion of the managing physician. In case of neutropenic fever, antibiotic therapy is indicated. Antimycotics and/or antivirals may also be indicated.
Monitoring of complete blood counts is essential during cyclophosphamide treatment so that the dose can be adjusted, if needed. Cyclophosphamide should not be administered to patients with neutrophils ≤ 1,500/mm³ and platelets < 50,000/mm³. Cyclophosphamide treatment may not be indicated, or should be interrupted, or the dose reduced, in patients who have or who develop a serious infection. G-CSF may be administered to reduce the risks of neutropenia complications associated with cyclophosphamide use. Primary and secondary prophylaxis with G-CSF should be considered in all patients considered to be at increased risk for neutropenia complications. The nadirs of the reduction in leukocyte count and thrombocyte count are usually reached in weeks 1 and 2 of treatment. Peripheral blood cell counts are expected to normalize after approximately 20 days. Bone marrow failure has been reported. Severe myelosuppression may be expected particularly in patients pretreated with and/or receiving concomitant chemotherapy and/or radiation therapy.
Urinary Tract and Renal Toxicity
Hemorrhagic cystitis, pyelitis, ureteritis, and hematuria have been reported with cyclophosphamide. Medical and/or surgical supportive treatment may be required to treat protracted cases of severe hemorrhagic cystitis. Discontinue cyclophosphamide therapy in case of severe hemorrhagic cystitis. Urotoxicity (bladder ulceration, necrosis, fibrosis, contracture and secondary cancer) may require interruption of cyclophosphamide treatment or cystectomy. Urotoxicity can be fatal. Urotoxicity can occur with short-term or long-term use of cyclophosphamide.
Before starting treatment, exclude or correct any urinary tract obstructions. Urinary sediment should be checked regularly for the presence of erythrocytes and other signs of urotoxicity and/or nephrotoxicity. Cyclophosphamide should be used with caution, if at all, in patients with active urinary tract infections. Aggressive hydration with forced diuresis and frequent bladder emptying can reduce the frequency and severity of bladder toxicity. Mesna has been used to prevent severe bladder toxicity.
Cardiotoxicity
Myocarditis, myopericarditis, pericardial effusion including cardiac tamponade, and congestive heart failure, which may be fatal, have been reported with cyclophosphamide therapy
Supraventricular arrhythmias (including atrial fibrillation and flutter) and ventricular arrhythmias (including severe QT prolongation associated with ventricular tachyarrhythmia) have been reported after treatment with regimens that included cyclophosphamide.
The risk of cardiotoxicity may be increased with high doses of cyclophosphamide, in patients with advanced age, and in patients with previous radiation treatment to the cardiac region and/or previous or concomitant treatment with other cardiotoxic agents.
Particular caution is necessary in patients with risk factors for cardiotoxicity and in patients with preexisting cardiac disease.
Monitor patients with risk factors for cardiotoxicity and with pre-existing cardiac disease.
Pulmonary Toxicity
Pneumonitis, pulmonary fibrosis, pulmonary veno-occlusive disease and other forms of pulmonary toxicity leading to respiratory failure have been reported during and following treatment with cyclophosphamide. Late onset pneumonitis (greater than 6 months after start of cyclophosphamide) appears to be associated with increased mortality. Pneumonitis may develop years after treatment with cyclophosphamide.
Monitor patients for signs and symptoms of pulmonary toxicity.
Secondary Malignancies
Cyclophosphamide is genotoxic. Secondary malignancies (urinary tract cancer, myelodysplasia, acute leukemias, lymphomas, thyroid cancer, and sarcomas) have been reported in patients treated with cyclophosphamide-containing regimens. The risk of bladder cancer may be reduced by prevention of hemorrhagic cystitis.
Veno-occlusive Liver Disease
Veno-occlusive liver disease (VOD) including fatal outcome has been reported in patients receiving cyclophosphamide-containing regimens. A cytoreductive regimen in preparation for bone marrow transplantation that consists of cyclophosphamide in combination with whole-body irradiation, busulfan, or other agents has been identified as a major risk factor. VOD has also been reported to develop gradually in patients receiving long-term low-dose immunosuppressive doses of cyclophosphamide. Other risk factors predisposing to the development of VOD include preexisting disturbances of hepatic function, previous radiation therapy of the abdomen, and a low performance status.
Embryo-Fetal Toxicity
Cyclophosphamide can cause fetal harm when administered to a pregnant woman. Exposure to cyclophosphamide during pregnancy may cause birth defects, miscarriage, fetal growth retardation, and fetotoxic effects in the newborn. Cyclophosphamide is teratogenic and embryo-fetal toxic in mice, rats, rabbits and monkeys.
Advise female patients of reproductive potential to avoid becoming pregnant and to use highly effective contraception during treatment and for up to 1 year after completion of therapy.
Infertility
Male and female reproductive function and fertility may be impaired in patients being treated with cyclophosphamide. Cyclophosphamide interferes with oogenesis and spermatogenesis. It may cause sterility in both sexes. Development of sterility appears to depend on the dose of cyclophosphamide, duration of therapy, and the state of gonadal function at the time of treatment. Cyclophosphamide-induced sterility may be irreversible in some patients. Advise patients on the potential risks for infertility.
Impairment of Wound Healing
Cyclophosphamide may interfere with normal wound healing.
Hyponatremia
Hyponatremia associated with increased total body water, acute water intoxication, and a syndrome resembling SIADH (syndrome of inappropriate secretion of antidiuretic hormone), which may be fatal, has been reported.
Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
Cyclophosphamide administered by different routes, including intravenous, subcutaneous or intraperitoneal injection, or in drinking water, caused tumors in both mice and rats. In addition to leukemia and lymphoma, benign and malignant tumors were found at various tissue sites, including urinary bladder, mammary gland, lung, liver, and injection site.
Cyclophosphamide was mutagenic and clastogenic in multiple in vitro and in vivo genetic toxicology studies.
Cyclophosphamide is genotoxic in male and female germ cells. Animal data indicate that exposure of oocytes to cyclophosphamide during follicular development may result in a decreased rate of implantations and viable pregnancies, and in an increased risk of malformations. Male mice and rats treated with cyclophosphamide show alterations in male reproductive organs (e.g., decreased weights, atrophy, changes in spermatogenesis), and decreases in reproductive potential (e.g., decreased implantations and increased post-implantation loss) and increases in fetal malformations when mated with untreated females.
Use In Specific Populations
Pregnancy
Pregnancy Category D - Risk Summary
Cyclophosphamide can cause fetal harm when administered to a pregnant woman based on its mechanism of action and published reports of effects in pregnant patients or animals. Exposure to cyclophosphamide during pregnancy may cause fetal malformations, miscarriage, fetal growth retardation, and toxic effects in the newborn. Cyclophosphamide is teratogenic and embryo-fetal toxic in mice, rats, rabbits and monkeys. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to a fetus.
Human Data
Malformations of the skeleton, palate, limbs and eyes as well as miscarriage have been reported after exposure to cyclophosphamide in the first trimester. Fetal growth retardation and toxic effects manifesting in the newborn, including leukopenia, anemia, pancytopenia, severe bone marrow hypoplasia, and gastroenteritis have been reported after exposure to cyclophosphamide.
Animal Data
Administration of cyclophosphamide to pregnant mice, rats, rabbits and monkeys during the period of organogenesis at doses at or below the dose in patients based on body surface area resulted in various malformations, which included neural tube defects, limb and digit defects and other skeletal anomalies, cleft lip and palate, and reduced skeletal ossification.
Nursing Mothers
Cyclophosphamide is present in breast milk. Neutropenia, thrombocytopenia, low hemoglobin, and diarrhea have been reported in infants breast fed by women treated with cyclophosphamide. Because of the potential for serious adverse reactions in nursing infants from cyclophosphamide, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Pediatric Use
Pre-pubescent girls treated with cyclophosphamide generally develop secondary sexual characteristics normally and have regular menses. Ovarian fibrosis with apparently complete loss of germ cells after prolonged cyclophosphamide treatment in late pre-pubescence has been reported. Girls treated with cyclophosphamide who have retained ovarian function after completing treatment are at increased risk of developing premature menopause.
Pre-pubescent boys treated with cyclophosphamide develop secondary sexual characteristics normally, but may have oligospermia or azoospermia and increased gonadotropin secretion. Some degree of testicular atrophy may occur. Cyclophosphamide-induced azoospermia is reversible in some patients, though the reversibility may not occur for several years after cessation of therapy.
Geriatric Use
There is insufficient data from clinical studies of cyclophosphamide available for patients 65 years of age and older to determine whether they respond differently than younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac functioning, and of concomitant disease or other drug therapy.
Females and Males of Reproductive Potential
Contraception
Pregnancy should be avoided during treatment with cyclophosphamide because of the risk of fetal harm.
Female patients of reproductive potential should use highly effective contraception during and for up to 1 year after completion of treatment.
Male patients who are sexually active with female partners who are or may become pregnant should use a condom during and for at least 4 months after treatment.
Infertility
Females
Amenorrhea, transient or permanent, associated with decreased estrogen and increased gonadotropin secretion develops in a proportion of women treated with cyclophosphamide. Affected patients generally resume regular menses within a few months after cessation of therapy. The risk of premature menopause with cyclophosphamide increases with age. Oligomenorrhea has also been reported in association with cyclophosphamide treatment.
Animal data suggest an increased risk of failed pregnancy and malformations may persist after discontinuation of cyclophosphamide as long as oocytes/follicles exist that were exposed to cyclophosphamide during any of their maturation phases. The exact duration of follicular development in humans is not known, but may be longer than 12 months.
Males
Men treated with cyclophosphamide may develop oligospermia or azoospermia which are normally associated with increased gonadotropin but normal testosterone secretion.
Use in Patients with Renal Impairment
In patients with severe renal impairment, decreased renal excretion may result in increased plasma levels of cyclophosphamide and its metabolites. This may result in increased toxicity. Monitor patients with severe renal impairment (CrCl =10 mL/min to 24 mL/min) for signs and symptoms of toxicity.
Cyclophosphamide and its metabolites are dialyzable although there are probably quantitative differences depending upon the dialysis system being used. In patients requiring dialysis, use of a consistent interval between cyclophosphamide administration and dialysis should be considered.
Use in Patients with Hepatic Impairment
Patients with severe hepatic impairment have reduced conversion of cyclophosphamide to the active 4hydroxyl metabolite, potentially reducing efficacy.
The following adverse reactions are discussed in more detail in other sections of the labeling.
- Hypersensitivity
- Myelosuppression, Immunosuppression, Bone Marrow Failure, and Infections
- Urinary Tract and Renal Toxicity
- Cardiotoxicity
- Pulmonary Toxicity
- Secondary Malignancies
- Veno-occlusive Liver Disease
- Embryo-Fetal Toxicity
- Reproductive System Toxicity
- Impaired Wound Healing
- Hyponatremia
Common Adverse Reactions
Hematopoietic system
Neutropenia occurs in patients treated with Ledoxan (cyclophosphamide). The degree of neutropenia is particularly important because it correlates with a reduction in resistance to infections. Fever without documented infection has been reported in neutropenic patients.
Gastrointestinal system
Nausea and vomiting occur with cyclophosphamide therapy. Anorexia and, less frequently, abdominal discomfort or pain and diarrhea may occur. There are isolated reports of hemorrhagic colitis, oral mucosal ulceration and jaundice occurring during therapy.
Skin and its structures
Alopecia occurs in patients treated with cyclophosphamide. Skin rash occurs occasionally in patients receiving the drug. Pigmentation of the skin and changes in nails can occur.
Postmarketing Experience
The following adverse reactions have been identified from clinical trials or post-marketing surveillance. Because they are reported from a population from unknown size, precise estimates of frequency cannot be made.
Cardiac: cardiac arrest, ventricular fibrillation, ventricular tachycardia, cardiogenic shock, pericardial effusion (progressing to cardiac tamponade), myocardial hemorrhage, myocardial infarction, cardiac failure (including fatal outcomes), cardiomyopathy, myocarditis, pericarditis, carditis, atrial fibrillation, supraventricular arrhythmia, ventricular arrhythmia, bradycardia, tachycardia, palpitations, QT prolongation.
Congenital, Familial and Genetic: intra-uterine death, fetal malformation, fetal growth retardation, fetal toxicity (including myelosuppression, gastroenteritis).
Ear and Labyrinth: deafness, hearing impaired, tinnitus.
Endocrine: water intoxication.
Eye: visual impairment, conjunctivitis, lacrimation.
Gastrointestinal: gastrointestinal hemorrhage, acute pancreatitis, colitis, enteritis, cecitis, stomatitis, constipation, parotid gland inflammation.
General Disorders and Administrative Site Conditions: multiorgan failure, general physical deterioration, influenza-like illness, injection/infusion site reactions (thrombosis, necrosis, phlebitis, inflammation, pain, swelling, erythema), pyrexia, edema, chest pain, mucosal inflammation, asthenia, pain, chills, fatigue, malaise, headache.
Hematologic: myelosuppression, bone marrow failure, disseminated intravascular coagulation and hemolytic uremic syndrome (with thrombotic microangiopathy).
Hepatic: veno-occlusive liver disease, cholestatic hepatitis, cytolytic hepatitis, hepatitis, cholestasis; hepatotoxicity with hepatic failure, hepatic encephalopathy, ascites, hepatomegaly, blood bilirubin increased, hepatic function abnormal, hepatic enzymes increased.
Immune: immunosuppression, anaphylactic shock and hypersensitivity reaction.
Infections: The following manifestations have been associated with myelosuppression and immunosuppression caused by cyclophosphamide: increased risk for and severity of pneumonias (including fatal outcomes), other bacterial, fungal, viral, protozoal and, parasitic infections; reactivation of latent infections, (including viral hepatitis, tuberculosis), Pneumocystis jiroveci, herpes zoster, Strongyloides, sepsis and septic shock.
Investigations: blood lactate dehydrogenase increased, C-reactive protein increased.
Metabolism and Nutrition: hyponatremia, fluid retention, blood glucose increased, blood glucose decreased.
Musculoskeletal and Connective Tissue: rhabdomyolysis, scleroderma, muscle spasms, myalgia, arthralgia.
Neoplasms: acute leukemia, myelodysplastic syndrome, lymphoma, sarcomas, renal cell carcinoma, renal pelvis cancer, bladder cancer, ureteric cancer, thyroid cancer.
Nervous System: encephalopathy, convulsion, dizziness, neurotoxicity has been reported and manifested as reversible posterior leukoencephalopathy syndrome, myelopathy, peripheral neuropathy, polyneuropathy, neuralgia, dysesthesia, hypoesthesia, paresthesia, tremor, dysgeusia, hypogeusia, parosmia.
Pregnancy: premature labor.
Psychiatric: confusional state.
Renal and Urinary: renal failure, renal tubular disorder, renal impairment, nephropathy toxic, hemorrhagic cystitis, bladder necrosis, cystitis ulcerative, bladder contracture, hematuria, nephrogenic diabetes insipidus, atypical urinary bladder epithelial cells.
Reproductive System: infertility, ovarian failure, ovarian disorder, amenorrhea, oligomenorrhea, testicular atrophy, azoospermia, oligospermia.
Respiratory: pulmonary veno-occlusive disease, acute respiratory distress syndrome, interstitial lung disease as manifested by respiratory failure (including fatal outcomes), obliterative bronchiolitis, organizing pneumonia, alveolitis allergic, pneumonitis, pulmonary hemorrhage; respiratory distress, pulmonary hypertension, pulmonary edema, pleural effusion, bronchospasm, dyspnea, hypoxia, cough, nasal congestion, nasal discomfort, oropharyngeal pain, rhinorrhea.
Skin and Subcutaneous Tissue: toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, palmar-plantar erythrodysesthesia syndrome, radiation recall dermatitis, toxic skin eruption, urticaria, dermatitis, blister, pruritus, erythema, nail disorder, facial swelling, hyperhidrosis.
Tumor lysis syndrome: like other cytotoxic drugs, cyclophosphamide may induce tumor-lysis syndrome and hyperuricemia in patients with rapidly growing tumors.
Vascular: pulmonary embolism, venous thrombosis, vasculitis, peripheral ischemia, hypertension, hypotension, flushing, hot flush.
No se conoce ningún antídoto específico para la ciclofosfamida.
La sobredosis debe manejarse con medidas de apoyo, incluido el tratamiento adecuado para cualquier infección concurrente, mielosupresión o toxicidad cardíaca en caso de que ocurra.
Las consecuencias graves de la sobredosis incluyen manifestaciones de toxicidades dependientes de la dosis, como mielosupresión, urotoxicidad, cardiotoxicidad (incluida insuficiencia cardíaca), enfermedad hepática venooclusiva y estomatitis.
Los pacientes que recibieron una sobredosis deben ser monitoreados de cerca para detectar toxicidades y toxicidad hematológica en particular.
El ledoxano (ciclofosfamida) y sus metabolitos son dializables. Por lo tanto, la hemodiálisis rápida está indicada cuando se trata cualquier sobredosis o intoxicación suicida o accidental.
La profilaxis de la cistitis con mesna puede ser útil para prevenir o limitar los efectos urotóxicos con sobredosis de ciclofosfamida.
El ledoxano (ciclofosfamida) se biotransforma principalmente en el hígado a metabolitos alquilantes activos mediante un sistema de oxidasa microsomal de función mixta. Estos metabolitos interfieren con el crecimiento de células malignas susceptibles de proliferación rápida.
Después de la administración IV, la vida media de eliminación (t ½) varía de 3 a 12 horas con valores de aclaramiento corporal total (CL) de 4 a 5.6 L / h. La farmacocinética es lineal en el rango de dosis utilizado clínicamente. Cuando se administró ciclofosfamida a 4.0 g / m² durante una infusión de 90 minutos, la eliminación saturable en paralelo con la eliminación renal de primer orden describe la cinética del fármaco.
Absorción
Después de la administración oral, las concentraciones máximas de ciclofosfamida ocurrieron a la hora. El área bajo la relación de curva para el medicamento después de la administración oral y IV (AUCpo: AUCiv) varió de 0.87 a 0.96.
Distribución
Aproximadamente el 20% de la ciclofosfamida está unida a proteínas, sin cambios dependientes de la dosis. Algunos metabolitos están unidos a proteínas en una medida superior al 60%. El volumen de distribución se aproxima al agua corporal total (30 a 50 L).
Metabolismo
El hígado es el sitio principal de activación de ciclofosfamida. Aproximadamente el 75% de la dosis administrada de ciclofosfamida se activa mediante el citocromo P450 microsomal hepático, incluidos CYP2A6, 2B6, 3A4, 3A5, 2C9, 2C18 y 2C19, y 2B6 muestra la mayor actividad de 4-hidroxilasa. La ciclofosfamida se activa para formar 4-hidroxiciclofosfamida, que está en equilibrio con su aldófamida de tautómero abierto. La 4-hidroxiciclofosfamida y la aldofosfamida pueden sufrir oxidación por aldehído deshidrogenasas para formar los metabolitos inactivos 4-cetociclofosfamida y carboxifosfamida, respectivamente. La aldofosfamida puede sufrir β-eliminación para formar metabolitos activos de mostaza fosforamida y acroleína. Esta conversión espontánea puede ser catalizada por albúmina y otras proteínas. Menos del 5% de la ciclofosfamida puede ser desintoxicada directamente por oxidación de la cadena lateral, lo que lleva a la formación de metabolitos inactivos 2-decloroetilciclofosfamida. A dosis altas, la fracción del compuesto original limpiado por 4-hidroxilación se reduce, lo que resulta en la eliminación no lineal de ciclofosfamida en pacientes. La ciclofosfamida parece inducir su propio metabolismo. La autoinducción produce un aumento en el aclaramiento total, una mayor formación de metabolitos de 4-hidroxilo y valores de t1 / 2 acortados después de la administración repetida a intervalos de 12 a 24 horas.
Eliminación
La ciclofosfamida se excreta principalmente como metabolitos. 10 a 20% se excreta sin cambios en la orina y 4% se excreta en la bilis después de la administración IV.
However, we will provide data for each active ingredient